3-Aminoalkyl-4-aryl-tetrahydroazepines

ABSTRACT

3-Aminoalkyl-4-aryl-1,5,6,7-tetrahydro-2H-azepines, e.g. those of the formula ##STR1## Ar&#39; = phenyl, thienyl, pyridyl or phenyl subst. by alkyl, alkoxy, alkylthio, halo or CF 3  ; 
     Am&#39; = NH 2 , (alkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, or benzyl)amino, its N-lower alkyl derivatives; alkyleneimino, morpholino or piperazino; 
     q = 0 or 1; 
     X = H 2  or 0; 
     R&#39;, R&#34; = H or alkyl; 
     and salts thereof are potassium-sparing diuretic agents.

This is a divisional of application Ser. No. 809,840 filed on June 24,1977, now U.S. Pat. No. 4,150,129.

SUMMARY OF THE INVENTION

The present invention concerns and has for its object the provision ofnew 3-aminoalkyl-4-aryl-1,5,6,7-tetrahydro-2H-azepines, preferably thosecorresponding to Formula I ##STR2## wherein Ar is unsubstituted phenyl,thienyl or pyridyl, or phenyl substituted by up to 3 members selectedfrom lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylthio,lower alkylenedioxy, halogeno or trifluoromethyl; m is an integer from 1to 7; C_(n) H_(2n) is lower alkylene separating the olefinic carbon fromthe nitrogen atom by 3 carbon atoms; X represents two hydrogens or oxo,R is hydrogen, lower alkyl or hydroxyalkyl and Am is amino, simple ormixed, mono- or di-lower (alkyl, alkenyl, alkynyl, hydroxyalkyl, 3 to 7ring-membered cycloalkyl or Ar-alkyl)amino; mono- or bicyclic, 5 to 7ring-membered lower alkyleneimino, or lower mono- (oxa, thia oraza)-alkyleneimino, a lower alkanoyl derivative or a therapeuticallyuseful acid addition salt thereof; as well as of correspondingpharmaceutical compositions and of methods for the preparation andapplication of these products, which are useful diuretic agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The phenyl radical Ar is preferably phenyl substituted by up to three,especially one or two, of the same or different members selected fromthe group consisting of lower alkyl, e.g. methyl, ethyl, n- or i-propylor -butyl; free, etherified or esterified hydroxy or mercapto, such aslower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy; loweralkylenedioxy, e.g. methylenedioxy or ethylidenedioxy; lower alkylthio,e.g. methylthio or ethylthio; halogeno, e.g. fluoro, chloro or bromo; ortrifluoromethyl. Preferred Ar-radicals are phenyl, (hydroxy)phenyl,(lower alkyl)-phenyl, mono- or di-(lower alkoxy)-phenyl,(halogeno)-phenyl or (trifluoromethyl)-phenyl.

The term "lower", referred to above and hereinafter in connection withorganic radicals or compounds, respectively, defines such with up to 7,preferably up to 4, carbon atoms.

The radical C_(m) H_(2m) is preferably ethylene or 1,2-propylene, butmay also stand for methylene, 1,3-propylene, 1,2-, 1,3- or 1,4-butylene,1,2-, 1,3- or 1,4-pentylene, -hexylene or -heptylene.

The lower alkylene radical C_(n) H_(2n) is preferably 1,3- propylene,but also represents 1,3-butylene, 1,3- or 2,4-pentylene.

An open or cyclic amino group Am is exemplified by amino, lower (alkyl,alkenyl, alkynyl or hydroxyalkyl)amino, e.g. (methyl, ethyl, n- ori-propyl, -butyl, -pentyl, -hexyl or -heptyl; allyl, 2- or 3-butenyl;propargyl, 2- or 3-butynyl; or 2-hydroxyethyl, 2- or3-hydroxypropyl)amino; (3 to 7 ring-membered cycloalkyl or Ar-loweralkyl)amino, e.g. (cyclopentyl, cyclohexyl; benzyl or phenethyl)amino;or the N-lower alkyl-derivatives of said sec. amino groups, e.g. theN-(methyl, ethyl, n- or i-propyl, -butyl, -pentyl, -hexyl or-heptyl)-derivatives thereof; 5 to 7 ring-membered mono- or bicycliclower alkyleneimino, e.g. pyrrolidino, piperidino, (1,4-, 1,5-, 1,6-,2,5-, 2,6- or 1,7-hexylene or -heptylene)imino; 2- or3-azabicyclo[3.2.2]nonyl or [4.3.1]decyl; or lower mono-oxa, thia oraza-alkyleneimino, e.g. morpholino, thiamorpholino, piperazino orN-(lower alkyl or hydroxyalkyl)-piperazino, e.g. N-(methyl, ethyl or2-hydroxyethyl)-piperazino.

The radical X is preferably oxo and R advantageously hydrogen, but alsolower alkyl or hydroxyalkyl, preferably methyl, ethyl, hydroxymethyl or2-hydroxyethyl.

The lower alkanoyl derivatives of said compounds of Formula I arepreferably those containing alkanoyl attached to a primary or secondaryamino group Am, and/or those wherein X═H₂ and R═H; e.g. the acetyl,propionyl or pivaloyl derivatives.

Salts of the compounds of Formula I are preferably addition salts of thetherapeutically useful inorganic or organic acids listed below.

The compounds of the invention exhibit valuable pharmacologicalproperties. Primarily they show diuretic, natri- and chloroiureticactivity with rapid onset of action, high urine but low potassiumexcretion levels. This can be demonstrated in animal tests using, forexample mammals, e.g. rats or dogs, as test objects. Such tests areperformed, for example, by administering the compounds of the inventionwithin a gelatin capsule to dogs, or in the form of aqueous solutions orstarchy suspensions by stomach tube to rats, in an oral dosage rangebetween about 0.5 and 100 mg/kg/day, preferably between about 1 and 50mg/kg/day, advantageously between about 5 and 25 mg/kg/day.Simultaneously the test animals may receive various salt loads enterallyor parenterally, for example various amounts of subcutaneously applied0.9% saline, e.g. 100 ml thereof per medium-sized dog (beagle). Urine isthen collected, e.g. at 2 hour intervals, with or withoutcatheterization, and its volume, sodium, potassium and chloride contentestimated and compared with that of the same untreated or saline-treatedanimals. Besides the anti-edematous utility, the compounds of theinvention can also be used as intermediates in the preparation of othervaluable products, primarily of pharmacologically active compounds orcompositions, e.g. as components of antihypertensive agents.

Preferred and highly diuretic are those compounds of Formula I in whichAr is phenyl, (lower alkyl)-phenyl, mono- or di-(lower alkoxy)-phenyl,(lower alkylthio)-phenyl, (halogeno)-phenyl or (trifluoromethyl)-phenyl,m is an integer from 1 to 7, C_(n) H_(2n) is 1,3-propylene or1,3-butylene, X represents two hydrogens or oxo, R is hydrogen, loweralkyl or hydroxyalkyl and Am is amino, lower (alkyl, alkenyl, alkynyl,hydroxyalkyl, 5 or 6 ring-membered cycloalkyl or phenyl-loweralkyl)amino, the N- lower alkyl-derivatives of said sec. amino groups; 5to 7 ring-membered lower alkyleneimino,morpholino, thiamorpholino,piperazino or N-(lower alkyl or hydroxyalkyl)-piperazino; the loweralkanoyl derivatives of said compounds wherein Am is prim. or sec. aminoor both X and R are hydrogen; or a therapeutically useful acid additionsalt thereof.

Especially valuable and suitable for said utility are compounds ofFormula II ##STR3## wherein Ar' is phenyl, (alkyl)-phenyl, mono- ordi-(alkoxy)-phenyl or (alkylthio)-phenyl wherein the alkyl contains upto 4 carbon atoms, (halogeno)-phenyl or (trifluoromethyl)-phenyl, Am' isamino, lower (alkyl, alkenyl, alkynyl, hydroxyalkyl, 5 or 6ring-membered cycloalkyl or benzyl)amino, the N-lower alkyl derivativesof said sec. amino groups, 5 to 7 ring-membered lower alkyleneimino,morpholino, thiamorpholino, piperazino or N-lower alkyl-piperazino; Xrepresents two hydrogens or oxo; each of R' and R" is hydrogen or alkylwith up to 4 carbon atoms and q is the integer 0 or 1; or atherapeutically useful acid addition salt thereof.

More preferred are compounds of Formula II, wherein Ar' is phenyl,tolyl, mono- or dimethoxyphenyl, methylthiophenyl, fluorophenyl,chlorophenyl or trifluoromethylphenyl; Am' is amino, (methyl, ethyl, n-or i-propyl, allyl, propargyl, 2-hydroxyethyl, cyclopentyl, cyclohexylor benzyl)amino, or the N-(methyl, ethyl, n- or i-propyl, -butyl,-pentyl, -hexyl or -heptyl)-derivatives of said sec. amino groups;pyrrolidino, piperidino, morpholino or N-methylpiperazino; X is oxo;each of R' and R" is hydrogen or methyl and q is one; or atherapeutically useful acid addition salt thereof.

Outstanding are compounds of Formula II, wherein Ar' is m- orp-methoxyphenyl, Am' is N-(methyl, ethyl, n- or i-propyl, allyl orpropargyl)-N-(methyl, ethyl, i-propyl or n-butyl)amino; pyrrolidino,piperidino or morpholino; X is oxo, R' is hydrogen or methyl, R" ismethyl and q is one; or a therapeutically useful acid addition saltthereof which, when given to rats or dogs at oral doses as low as1.25-10 mg/kg/day, exhibit marked diuretic, natri- and chloriureticeffects.

The compounds of the invention are prepared according to methods inthemselves known. Advantageously they are obtained by: (a) reducingSchiff's bases or oximes obtained from compounds of Formula III ##STR4##or reducing nitriles or amides of Formula IV ##STR5## wherein Y is CN orCOAm and, if desired, converting any resulting compound into anothercompound of the invention.

Said reduction is carried out according to known methods, for examplewith the use of hydrogen in the presence of catalysts, e.g. platinum ornickel catalysts, or with nascent hydrogen, e.g. generatedelectrolytically, advantageously in case of said Schiff's bases oroximes. Also reducing agents are useful for both of said ketone- oracid-derived starting materials, preferably simple or complex lightmetal hydrides, such as lithium aluminum hydride, alane, boranes orsodium cyanoborohydride under appropriate conditions to either preservea carbonyl group in 2-position; i.e. to preserve X═O, or convert X═O toX═H₂.

The starting material is new and compounds of Formula III exhibitvaluable pharmacological properties also, for example antiallergiceffects, as can be demonstrated in the passive cutaneous anaphylaxistest according to J. Carr; J. Path. 108, 1 (1972). They are preferablyprepared by adding 2-Ar-1-pyrrolines to butenolides, preferablyα-angelicalactone (for compounds of Formula II), either in the absenceor presence of diluents, such as hydrocarbons or esters, e.g. toluene,xylene or ethyl acetate, advantageously at elevated temperatures, e.g.between 80° and 140°. Said nitriles or amides of Formula IV areadvantageously prepared from those of Formula II wherein Am' ismonoalkylamino by reaction with butyl lithium, followed by cyanogenbromide or carbon dioxide and amidizing the resulting acid with HAm anddiimidazolylcarbonyl.

Another process for preparing the compounds of the invention consists incondensing reaction esters of Formula V ##STR6## wherein Z is areactively esterified hydroxy group, for example, such esterified by astrong inorganic or organic acid, above all a hydrohalic acid, e.g.hydrochloric, hydrobromic or hydriodic acid; sulfuric or an aromaticsulfonic acid, e.g. p-toluene or m-bromobenzene sulfonic acid. Saidcondensation is preferably carried out in the presence or absence of abasic agent, such as an alkali or alkaline earth metal hydroxide,carbonate or bicarbonate, e.g. sodium, potassium or calcium hydroxide orcarbonate; alkali metal hydrides, lower alkoxides or alkanoates, e.g.sodium hydride, methylate or acetate, as well as organic tertiarynitrogen bases, such as tri-lower alkylamines or pyridines, e.g.triethylamine or lutidine.

The starting material of Formula V can be prepared by reducing thecompounds of Formula III to the corresponding alcohols, e.g. with sodiumborohydride, and reactively esterifying them with said inorganic ororganic acids, or reactive derivatives thereof, e.g. phosphorustrihalides or sulfonyl halides. Variously compounds of Formula V,wherein Z is hydrogen and m is 1, can be lithiated, e.g. with n-butyllithium, and reacted with lower alkyl disulfides, to yield compounds Vwith Z being lower alkylthio. These, in turn, can be converted intothose with Z being halogen, by cleaving them with sulfuryl halides; e.g.sulfuryl chloride.

The compounds of the invention thus obtained can be converted into eachother according to conventional methods. For example, resultingphenolethers may be hydrolyzed with hydrobromic acid or borontribromide, or prim. or sec. amines reacted with reactive esters of therespective alcohols, preferably derived from hydrohalic, aliphatic oraromatic sulfonic acids, e.g. lower alkyl sulfonates, e.g. the mesylateor tosylate, or with corresponding aldehydes or ketones and reducingagents, e.g. formic acid or sodium cyanoborohydride, in order to obtainsec. or tert. amines, respectively. Acyl-derivatives of prim. or sec.amines are obtained by conventional acylation with reactive acidderivatives, e.g. anhydrides or halides. Resulting acyl derivatives, orcompounds of Formula I with X═O, can be reduced as shown for the amidesof Formula IV, e.g. mildly with said simple hydrides, such as alane orboranes in order to retain X═O, or with stronger complex metal hydrides,e.g. lithium aluminum hydride, in order to obtain compounds with X═H₂.

Finally, a resulting base can be converted into a corresponding acidaddition salt, preferably with the use of a therapeutically acceptableacid or anion exchange preparation; or resulting salts can be convertedinto the corresponding free bases, for example, with the use of a base,such as a metal hydroxide, basic salt, ammonia, amine or cation exchangepreparation, e.g. an alkali metal hydroxide or carbonate. Said acidaddition salts are preferably such of therapeutically useful inorganicacids, such as strong metalloidic acids, for example, hydrohalic, e.g.hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric orperchloric acid; aliphatic or aromatic carboxylic or sulfonic acids,e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic, phenylaceticbenzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic,embonic, nicotinic; methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, benzenesulfonic, halogen-benzenesulfonic,toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamicacid.

These or other salts, for example, the picrates or tetrafluoroborates,can also be used for purification of the bases obtained; the bases areconverted into salts, the salts are separated and the bases areliberated from the salts. In view of the close relationship between thefree compounds and the compounds in the form of their salts, whenever acompound is referred to in this context, a corresponding salt is alsointended, provided such is possible or appropriate under thecircumstances. Resulting mixtures of isomers, e.g. diastereo or opticalisomers, can be separated into the single isomers by methods inthemselves known, e.g. by fractional distillation, crystallizationand/or chromatography, or separation of diastereomeric salts. As isobvious from Formula II, the carbon atom in the CHAm'-moiety (R" is nothydrogen) is an asymmetric carbon atom, yielding racemates.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Mainlythose starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being especially valuable.

The above reactions are carried out according to standard methods, inthe presence or absence of diluents, preferably such as are inert to thereagents are are solvents thereof of catalysts, condensing orneutralizing agents and/or inert atmospheres, at low temperatures, roomtemperature or advantageously elevated temperatures, at atmospheric orsuperatmospheric pressure.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinyl-pyrrolidone, if desired, (d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, enzymes of the binders oreffervescent mixtures and/or (e) absorbents, colorants, flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously fattyemulsions or suspensions. They may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promotors, salts for regulating the osmotic pressureand/or buffers. They may also contain other therapeutically valuablesubstances. Said pharmaceutical compositions are parpared according toconventional mixing, granulating or coating methods respectively andcontain about 0.1 to 75%, preferably about 1 to 50% of the activeingredient.

The following examples, illustrating the invention, are not to beconstrued as being limitations thereon. Temperatures are given indegrees Centigrade and all parts wherever given are parts by weight. Ifnot mentioned otherwise, all evaporations are performed under reducedpressure, e.g. between about 15 and 100 mmHg.

EXAMPLE 1

The solution of 8.0 g of3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 14.95 gof piperidine, 6.6 ml of 5 N methanolic hydrogen chloride and 1.9 g ofsodium cyanoborohydride in 120 ml of methanol is refluxed overnight. Anadditional portion of 0.95 g of sodium cyanoborohydride is added andrefluxing continued for 24 hours. The mixture is cooled to 0°, 30 ml ofconcentrated hydrochloric acid are added and the solution concentrated.The concentrate is diluted with 100 ml of water, the solution washedwith benzene and rendered basic with 70 ml of 3 N aqueous sodiumhydroxide. It is extracted with diethyl ether, the extract evaporatedand the residue crystallized from petroleum ether and hexane, to yieldthe3-(2-piperidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinoneof the formula ##STR7## melting at 97° to 99°.

The starting material is prepared as follows: The solution of 70 g of2-(3-methoxyphenyl)-1-pyrroline [J. Org. Chem. 23, 1278, 1281 (1958)]and 43.2 g of α-angelicalactone in 600 ml of toluene is refluxedovernight. A second portion of 43.2 g of α-angelicalactone is added, themixture is again refluxed overnight, cooled and evaporated. The residueis crystallized from 50 ml of ethyl acetate, to yield the3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, meltingat 140°-142°.

EXAMPLE 2

The solution of 1.36 g of3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 0.52 gof pyrrolidine and 0.1 g of p-toluenesulfonic acid hydrate in 10 ml ofbenzene is refluxed with water separation for 4 hours and evaporated.The residue is dissolved in 15 ml of ethanol and the solutionhydrogenated over 0.1 g of platinum oxide at atmospheric pressure androom temperature. The mixture is filtered, the filtrate evaporated andthe resulting oil dissolved in 2 N hydrochloric acid. The solution iswashed with benzene, basified with 3 N aqueous sodium hydroxide andextracted with diethyl ether. The extract is dried, evaporated and theresidue recrystallized from petroleum ether and hexane, to yield the3-(2-pyrrolidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 94° to 96°.

EXAMPLE 3

The solution of 1.3 g of3-(2-hydroxyiminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonein 60 ml of ethanol is hydrogenated in the presence of 0.5 g of Raneynickel at room temperature and atmospheric pressure. It is filtered, thefiltrate evaporated the residue treated with about 2 ml of ethanolichydrochloric acid, crystallized from ethanol-acetone and recrystallizedfrom ethanol, to yield the3-(2-aminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonehydrochloride melting at 217°-219°.

The starting material is prepared as follows: The mixture of 7.0 g of3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 3.88 gof potassium carbonate, 3.55 g of hydroxylamine hydrochloride, 5 ml ofwater and 60 ml of methanol is refluxed for 5 hours and then stirred atroom temperature overnight. 80 ml of water are added, the precipitatecollected and washed with ethanol and diethyl ether, to yield the3-(2-hydroxyiminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone,melting at 155°-158°.

EXAMPLE 4

The solution of 8.0 g of1-methyl-3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone,14.2 g of piperidine, 6.4 ml of 5 N methanolic hydrogen chloride and1.91 g of sodium cyanoborohydride in 100 ml of methanol is refluxedovernight. An additional portion of 1.91 g of sodium cyanoborohydride isadded and refluxing continued for another day. The solution is cooled,acidified with 35 ml of concentrated hydrochloric acid and evaporated.The residue is diluted with 100 ml of water, the aqueous solution washedwith benzene, filtered, basified with 65 ml 3 N aqueous sodium hydroxideand extracted with diethyl ether. The extract is dried, evaporated andthe residue crystallized from petroleum ether and recrystallized fromhexane, to yield the1-methyl-3-(2-piperidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 101°-103°.

The starting material is prepared as follows: The solution of 27.2 g of3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 31 g ofethylene glycol and 0.2 g of p-toluene-sulfonic acid hydrate in 200 mlof benzene is refluxed with a water separator for 7 hours. It is cooledto 0°, 100 ml of 5% aqueous sodium bicarbonate are added and the benzenelayer separated. It is washed with water, dried, evaporated and theresidue crystallized from diethyl ether to give the3-(2-ethylenedioxypropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 132°-134°.

To the solution of 27.0 g thereof in 110 ml of dimethylformamide, 5.4 gof a 57% suspension of sodium hydride in mineral oil are added and themixture is stirred at room temperature for 2 hours. The solution of 28.4ml of methyl iodide in 20 ml of dimethylformamide is added dropwise atroom temperature and the mixture stirred at room temperature overnight.It is poured onto 500 g of ice, the precipitate collected and washedwith water, to yield the1-methyl-3-(2-ethylenedioxypropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 113°-115°.

The suspension of 20 g thereof in a mixture of 150 ml of ethanol and 150ml of 0.2 N hydrochloric acid is stirred at room temperature for 3 days.It is concentrated at room temperature, the separated oil extracted withchloroform, the extract dried and evaporated, to give the1-methyl-3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7,-tetrahydro-2H-azepinoneshowing an I.R.-band at 1700 cm⁻¹.

EXAMPLE 5

The solution of 15.1 g of3-acetonyl-4-(3,4-dimethoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 25.5ml of isopropylamine 10 ml of 5.8 N methanolic hydrogen chloride and 3.4g of sodium cyanoborohydride in 260 ml of methanol is refluxed for 3days. The mixture is cooled, acidified to pH=1 with concentratedhydrochloric acid, evaporated and the residue diluted with water. It iswashed with ether, basified with 3 N aqueous sodium hydroxide to pH=11and extracted with diethyl ether. The extract is dried, evaporated andthe residue dissolved in 75 ml of acetone. The solution is treated with4.4 N ethanolic hydrogen chloride, and the precipitate collected, toyield the3-(2-isopropylaminopropyl)-4-(3,4-dimethoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonehydrochloride monohydrate melting at 135°-138°.

The starting material is prepared as shown in Example 1, it melts at137°-140°.

EXAMPLE 6

The mixture of 22.1 g of3-(2-piperidinopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinoneand 128 ml of 48% hydrobromic acid is stirred under reflux for sixhours. It is cooled, basified with concentrated ammonia and extractedwith chloroform. The extract is dried, evaporated, the residuecrystallized from diethyl ether and recrystallized from acetone, toyield the3-(2-piperidinopropyl)4-(4-hydroxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 178°-181°.

EXAMPLE 7

The solution of 1.0 g of3-(2-hydroxyiminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone(Example 3) in 10 ml of tetrahydrofuran is treated with 8.7 ml of Molaralanetriethylamine in benzene while stirring at 0° C. After 2 hours themixture is stirred at room temperature overnight and subsequentlyrefluxed for 3 hours after addition of 10 ml of benzene. The mixture isagain cooled in an ice bath, treated first with 5 ml of water, then 5 mlof 3 N aqueous sodium hydroxide and the organic layer is separated. Theaqueous solution is extracted with benzene, the combined organic layeris dried, evaporated and the residue is dissolved in 10 ml of 6 Nhydrochloric acid. The solution is washed with benzene, basified with 3N aqueous sodium hydroxide and extracted with methylene chloride. Theextract is evaporated, the residue dissolved in diethyl ether and 0.45ml of 8 N ethanolic hydrogen chloride are added. The resulting solid iscollected and recrystallized from acetone-ethanol, to give3-(2-aminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinedihydrochloride melting at 246°-248° C.

EXAMPLE 8

The solution of 13.6 g of3-acetonyl-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 25.5 mlof isopropylamine, 10 ml of 5.8 N methanolic hydrogen chloride and 3.4 gof sodium cyanoborohydride in 260 ml of methanol is refluxed for threedays. The mixture is cooled to 0°, acidified to pH=1 with concentratedhydrochloric acid and evaporated. The residue is taken up in water, themixture washed with diethyl ether, rendered basic to pH=10-11 with 3 Naqueous sodium hydroxide and extracted with diethyl ether. The extractis dried, evaporated and 13.5 g of the residual free base is dissolvedin 80 ml of acetone. The solution is treated with 10.5 ml of 4.4 Nethanolic hydrochloric acid, the mixture evaporated, the residuecrystallized from diethyl ether and recrystallized fromisopropanol-ethyl acetate, to yield the3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonehydrochloride hemihydrate melting at 165°-167°.

The3-(2-isopropylaminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinoneis similarly prepared. It shows major I.R.-bands at 1650, 3150 and 3350cm⁻¹ (in chloroform).

EXAMPLE 9

4.78 ml of glacial acetic acid are added dropwise to the ice-cooledmixture of 7.6 g of3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone,13.3 ml of acetaldehyde, 4.5 g of sodium cyanoborohydride and 90 ml ofacetonitrile. The mixture is stirred at room temperature for 90 minutes,cooled in an ice-bath, acidified to pH=1 with concentrated hydrochloricacid and evaporated. The residue is taken up in 150 ml of water, thesolution washed with diethyl ether, filtered, basified with 3 N aqueoussodium hydroxide and extracted with diethyl ether. The extract is dried,evaporated, the residue crystallized from petroleum ether and furtherpurified by suspension in hexane, to yield the3-[2-(N-isopropyl-N-ethylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 64°-66°.

Similarly prepared is the3-[2-(N-isopropyl-N-ethylamino)-propyl]-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 86°-88°.

By substituting propionaldehyde for acetaldehyde one obtains the3-[2-(N-isopropyl-N-n-propylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 90°-92°.

EXAMPLE 10

The mixture of 6.3 g of3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone,20 ml of ethylene oxide and 25 ml of absolute ethanol is stirred in asealed vessel at room temperature for 5 days. The resulting solution isevaporated, the residue crystallized from petrolem ether andrecrystallized from ethyl acetate-hexane, to yield the3-[2-(N-isopropyl-N-hydroxyethylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 109°-111°.

EXAMPLE 11

The mixture of 8.23 g of3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone,2.25 ml of methyl iodide, 3.59 g of potassium carbonate and 100 ml ofabsolute ethanol is refluxed for five hours and evaporated. The residueis suspended in 100 ml of water and the suspension extracted withdiethyl ether. The extract is dried, evaporated and the residuecrystallized from ethanol-water to yield the3-[2-(N-isopropyl-N-methylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 86°-88°.

Starting with allyl bromide, the3-[2-(N-isopropyl-N-allylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinoneis prepared in analogous fashion; it melts at 95°-97°.

EXAMPLE 12

The solution of 6.5 g of3-(2-methoxyiminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonein 150 ml of ethanol is hydrogenated at room temperature and atmosphericpressure in the presence of 10 g of Raney nickel until the uptake of 2mole equivalents of hydrogen is complete. The mixture is filtered, thefiltrate evaporated and the residue dissolved in 100 ml of water and 10ml of 6 N hydrochloric acid. The acidic solution is washed with diethylether, filtered, basified with 30 ml of 3 N aqueous sodium hydroxide andrepeatedly extracted with chloroform. The extract is dried, evaporatedand the residue is purified by suspension in diethyl ether, to give the3-(2-aminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 131°-133°.

The starting material is prepared as follows: 2.8 g of methoxyaminehydrochloride are added to the solution of 9.1 g of3-acetonyl-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone in amixture of 200 ml of absolute ethanol and 100 ml of pyridine. Thesolution is stirred at room temperature overnight and poured into 3000ml of ice-water. The mixture is stirred for two hours, the resultingprecipitate collected and dried, to yield said O-methyloxime melting at121°-123°.

EXAMPLE 13

The solution of 6.15 g of3-(2-piperidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonein 60 ml of methylene chloride, cooled in a dry ice-acetone bath, isadded slowly to 120 ml of a similarly precooled 10% solution of borontribromide in methylene chloride. The mixture is allowed to warm to roomtemperature and stirred for four hours. It is again cooled in an icebath, 120 ml of 3 N aqueous sodium hydroxide are added and stirring atroom temperature is continued for 30 minutes. The aqueous layer isseparated and the methylene chloride solution is washed with 60 ml ofwater. The combined aqueous solution is neutralized to pH=9-10 with 6 Nhydrochloric acid and the precipitate collected, to yield the3-(2-piperidinopropyl)-4-(3-hydroxyphenyl)-1,5,6,7-tetrahydro-2H-azepinonemelting at 218°-220°.

EXAMPLE 14

According to the methods illustrated by the previous examples, thefollowing compounds of Formula II are prepared from equivalent amountsof the corresponding starting materials: R"=CH₃, X=O and q=l:

    __________________________________________________________________________    No.                                                                              Ar'        Am'         R' Salt   m.p. ° C.                          __________________________________________________________________________    1  phenyl     isopropylamino                                                                            H  --      95-7                                     2  "          dimethylamino                                                                             H  --     145-7                                     3  "          piperidino  H  --     143-5                                     4  "          morpholino  H  --     138-0                                     5  4-CH.sub.3C.sub.6 H.sub.4                                                                piperidino  H  --     136-8                                     6  2-CH.sub.3 OC.sub.6 H.sub.4                                                              "           H  HCl . 1/3 H.sub.2 O                                                                  168-0                                     7  3-CH.sub.3 OC.sub.6 H.sub.4                                                              dimethylamino                                                                             H  --     110-2                                     8  "          "           CH.sub.3                                                                         HCl    150-2                                     9  "          4-CH.sub.3 -piperidino                                                                    H  --     125-7                                     10 "          3,5-(CH.sub.3).sub.2 -piperidino                                                          H  --     133-5                                     11 "                                                                                         ##STR8##   H  --     103-5                                     12 "                                                                                         ##STR9##   H  --     109-1                                     13 3-CH.sub.3 -4-CH.sub.3 OC.sub.6 H.sub.3                                                  isopropylamino                                                                            H  --      85- 8                                    14 4-CH.sub.3 OC.sub.6 H.sub.4                                                              dimethylamino                                                                             H  --     116-8                                     15 "          piperidino  H  --     115-8                                     16 4-FC.sub.6 H.sub.4                                                                       dimethylamino                                                                             H  --     140-2                                     17 "          piperidino  H  --     142-4                                     18 4-ClC.sub.6 H.sub.4                                                                      dimethylamino                                                                             H  --     145-6                                     19 "          isopropylamino                                                                            H  --     117-9                                     20 "          cyclohexylamino                                                                           H  --     148-0                                     21 "          piperidino  H  --     144-6                                     22 3,4-(CH.sub.3 O).sub.2C.sub.6 H.sub.3                                                    isopropylamino                                                                            H  HCl . H.sub.2 O                                                                      135-8                                     23 "          dimethylamino                                                                             H  --      68-0                                     24 3-Cl-4-CH.sub.3 OC.sub.6 H.sub.3                                                         piperidino  H  --     164-6                                     25 "          diethylamino                                                                              H  --     107-9                                     26 4-HOC.sub.6 H.sub.4                                                                      piperidino  H  --     178-1                                     27 2-thienyl  "           H  --     133-5                                     28 3-pyridyl  "           H  --     159-1                                     29 2-thienyl  C.sub.2 H.sub.5NCH(CH.sub.3).sub.2                                                        H  --      76-8                                     30 4-CH.sub.3 OC.sub.6 H.sub.4                                                              "           H  --      64-6                                     31 "          "           CH.sub.3                                                                         --      69-1                                     32 "          N(C.sub.2 H.sub.5).sub.2                                                                  H  --     111-3                                     33 "          N(nC.sub.3 H.sub.7).sub.2                                                                 H  --      87-9                                     34 "          CH.sub.3NC.sub.2 H.sub.5                                                                  H  --      97-9                                     35 "          CH.sub.3NCH(CH.sub.3).sub.2                                                               H  --      86-8                                     36 "          4-CH.sub.3 -piperazino                                                                    H  --     148-0                                     __________________________________________________________________________

The ketonic starting materials are new and are prepared as illustratedby Example 1. Following are the melting points of said ketones yieldingthe above-numbered final products: No. 1-4 160°-3°; 5: 162°-4°; 6:153°-5°; 7-12: 140°-2°; 1-15: 156°-9°; 16,17: 138°-0°; 18-21: 122°-6°;22,23: 137°-0°; 24,25: 139°-1°; 26: 189°-1°; 27: 139°-1°; 28: 116°-9°;13: 157°-9°.

EXAMPLE 15

Preparation of 10,000 tablets each containing 100.0 mg of the activeingredient:

Formula

    ______________________________________                                        3-[2-(N-ethyl-N-isopropylamino)-propyl]-4-                                    (4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone                                                       1,000.00 g                                          Lactose                   2,535.00 g                                          Corn starch               125.00   g                                          Polyethylene glycol 6,000 150.00   g                                          Talcum powder             150.00   g                                          Magnesium stearate        40.00    g                                          Purified water            q.s.                                                ______________________________________                                    

Procedure

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance, lactose, talcum, magnesium stearate and half ofthe starch are mixed in a suitable mixer. The other half of the starchis suspended in 65 ml of water and the suspension added to the boilingsolution of the polyethylene glycol in 260 ml of water. The paste formedis added to the powders which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35°,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 10.3 mm diameter, uppers bisected.

Preparation of 10,000 capsules each containing 50.0 mg of the activeingredient:

Formula

    ______________________________________                                        3-[2-(N-ethyl-N-isopropylamino)-propyl]-4-                                    (4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone                                                       500.0    g                                          Lactose                   2,350.0  g                                          Talcum powder             150.0    g                                          ______________________________________                                    

Procedure

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance is placed in a suitable mixer and mixed firstwith the talcum, then with the lactose until homogenous. No. 2 capsulesare filled with 300 mg of the mixture, using a capsule filling machine.

Analogously, tablets and capsules are prepared from the other compoundsillustrated in the previous examples.

I claim:
 1. A 3-aminoalkyl-4-aryl-1,5,6,7-tetrahydro-2H-azepinone of theformula ##STR10## wherein Ar is unsubstituted phenyl, thienyl orpyridyl, or phenyl substituted by up to 3 members selected from loweralkyl, hydroxy, mercapto, lower alkoxy, lower alkylthio, loweralkylenedioxy, halogeno or trifluoromethyl; m is an integer from 1 to 7;C_(n) H_(2n) is lower alkylene separating the olefinic carbon from thenitrogen atom by 3 carbon atoms; R is hydrogen, lower alkyl or lowerhydroxyalkyl and Am is mono- or bi-cyclic, 5 to 7 ring-membered loweralkyleneimino, or lower mono- (oxa, thia or aza)alkyleneinimo, a loweralkanoyl derivative of said compounds wherein R is hydrogen, or atherapeutically useful acid addition salt thereof.
 2. A compound asclaimed in claim 1, in which formula Ar is phenyl, (lower alkyl)-phenyl,mono- or di-(lower alkoxy)-phenyl, (lower alkylthio)-phenyl,(halogeno)-phenyl or (trifluoromethyl)-phenyl, m is an integer from 1 to7, C_(n) H_(2n) is 1,3-propylene or 1,3-butylene, R is hydrogen, loweralkyl or lower hydroxyalkyl and Am is 5 to 7 ring-membered loweralkyleneimino, morpholino, thiamorpholino, piperazino or N-(lower alkylor hydroxyalkyl)-piperazino; the lower alkanoyl derivatives of saidcompounds wherein R is hydrogen; or a therapeutically useful acidaddition salt thereof.
 3. A compound as claimed in claim 1, andcorresponding to the formula ##STR11## wherein Ar' is phenyl,(alkyl)-phenyl, mono- or di-(alkoxy)phenyl or (alkylthio)-phenyl,wherein the alkyl contains up to 4 carbon atoms, (halogeno)-phenyl or(trifluoromethyl)-phenyl); Am' is 5 to 7 ring-membered loweralkyleneimino, morpholino, thiamorpholino, piperazino or N-loweralkyl-piperazino; each of R' and R" is hydrogen or alkyl with up to 4carbon atoms and q is the integer 0 or 1; or a therapeutically usefulacid addition salt thereof.
 4. A compound as claimed in claim 3, inwhich formula Ar' is phenyl, tolyl, mono- or dimethoxyphenyl,methylthiophenyl, fluorophenyl, chlorophenyl or trifluoromethylphenyl;Am' is pyrrolidino, piperidino, morpholino or N-methylpiperazino; eachof R' and R" is hydrogen or methyl and q is one; or a therapeuticallyuseful acid addition salt thereof.
 5. A compound as claimed in claim 3,in which formula Ar' is m- or p-methoxyphenyl, Am' is; pyrrolidino,piperidino or morpholino; X is oxo, R' hydrogen or methyl, R" is methyland q is one; or a therapeutically useful acid addition salt thereof. 6.A compound as claimed in claim 3, and being the3-(2-piperidinopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone,or a therapeutically useful acid addition salt thereof.
 7. A diuretic orantihypertensive pharmaceutical composition comprising a diuretically orantihypertensively effective amount of a compound as claimed in claim 1,together with a pharmaceutical excipient.
 8. A method of treatingedematous or hypertensive conditions in a mammal, which comprises theenteral or parenteral administration to said mammal of a composition asclaimed in claim 7.